Organisms exposed to ionizing radiations are mainly damaged by free radicals, which are generated by the radiolysis of water contained in the cells.
The superoxide dismutase (SOD) family of proteins is necessary to protect oxygen-utilizing cells from the toxicity of the reactive oxygen species (ROS) produced during normal metabolism. Besides being protective proteins, these enzymes are also key components of signalling pathways that regulate cell physiology. SODs catalyze the reaction: with hydrogen peroxide being then removed by catalases (CATs) and peroxidases, of which glutathione peroxidase (GPx) has been the most widely studied. There are three known forms of SOD in mammalian cells: a copper- and zinc-containing superoxide dismutase (CuZnSOD) found mainly in the cytoplasm and in the nucleus, a manganese-containing superoxide dismutase (MnSOD) found in the mitochondria, and an extracellular superoxide dismutase (ecSOD) found primarily in the extracellular compartments. The superoxide dismutase are enzymes of remarkable pharmacological interest for their potential role in the prevention of all pathologies involving oxidative damage. It has been recently proposed that these enzymes can be useful in the prevention and in the treatment of damages caused by physical agents and, particularly by ionizing radiations (1) which generate high levels of free radicals (2-6).
The large scientific and practical interest toward MnSOD has resulted in intensive developments of new technologies for its production but, despite great efforts, efficient production of recombinant human SOD in prokaryotic systems or simple eukaryotes failed. This failure has so far hindered its large-scale production and protein genetic engineering (7). Recently a new technology for radio-protective gene therapy using the transgene for the antioxidant manganese superoxide dismutase, delivered to specific target organs (lung, esophagus, oral cavity, oropharynx, and bladder) using gene transfer vectors including plasmid/liposomes (PL) and adenovirus was developed. Significant reduction of organ specific tissue injury has been demonstrated in several organ systems in rodent models.
Moreover, the application of MnSOD-PL gene therapy in the setting of fractionated chemo-radiotherapy is being tested in clinical trials for the prevention of esophagitis during the treatment of lung non-small-cells carcinoma, and in the prevention of mucositis during combination therapy of carcinomas of the head and neck. Encouraging results in pre-clinical models have suggested that radioprotective gene therapy may facilitate dose escalation protocols to allow increases in the therapeutic ratio of cancer radiotherapy (8).
Recently a significant reduction of tissue injury from irradiation damages was demonstrated by using the MnSOD-plasmid/liposome treatments in the protection of murine lung.